1. Field of the Invention
The present invention relates generally to the fields of organic chemistry and anti-tumor compounds. More specifically, the present invention relates to the asymmetric synthesis of (S,R.R)-(xe2x88x92)-actinonin and derivatives and analogs thereof and their uses as anti-tumor agents.
2. Description of the Related Art
(S,S,R)-(xe2x88x92)-Actinonin (1), was first isolated by Green and Singh from the Malayan strain of Actinomycete, Streptomyces sp. Cutter 12 (N.C.I.B. 8845) (FIG. 1). It has been shown that actinonin exhibits antibiotic and anti-tumor properties (1-7). Studies have demonstrated that actinonin exhibits cytotoxicity towards tumor cell lines in vitro (4). Furthermore, actinonin induces GI arrest and apoptosis in human leukemia and lymphoma cells. It also treats AKR leukemia in AKR mice with minimal toxicity.
Although actinonin is commercially available and usually extracted from Actinomycete and Streptomyces bacteria, specifically Streptomyces roseopallidus (9, 10), the yield of compound derived is miniscule. For example, out of a typical ten day culture that yields eleven liters of filtrate, only 146 mg of pure actinonin are isolated. Currently, actinonin is synthesized by either of two synthetic schema. In Ollis"" 1975 synthetic method, the synthesis of actinonin is non-stereoselective and the diastereomers have to be separated; difficult process producing small yields (11). Davies"" 1992 synthesis is stereoselective and represents the first asymmetric synthesis of (xe2x88x92)-actinonin. An Fe(II)-based chiral auxiliary is used to introduce chirality at the xcex1-position of a carboxylic acid (13,14). However, this process causes disposal problems and therefore commercialization of the synthetic (xe2x88x92)-actinonin is doubtful. It is therefore necessary to develop a method for multi-gram synthesis of actinonin for further testing in various cancer cell lines and for animal studies.
The prior art is deficient in the lack of effective means of asymmetically synthesizing (S,R,R)-(xe2x88x92)-actinonin, its derivatives and its analogs for use as anti-tumor agents. The present invention fulfills this long-standing need and desire in the art.
One embodiment of the present invention provides a chemical compound comprising an analog or a derivative of (S,S,R)-(xe2x88x92)-actinonin having the structure: 
where R1 is an optionally substituted or halogenated alkyl, aryl, heteroalkyl or heteroaryl amine, where R1 further comprises a cyclic or bicyclic structure; R2 is methyl, CH2CH3, (CH2)2CH3, C(CH3)3, phenyl, 3,4-dichlorophenyl, biphenyl, benzyl, 4-hydroxybenzyl, piperidine, N-Boc-4-piperidine, CH2-(N-Boc-4-piperidine), 4-tetrahydropyran, CH2-4-tetrahydropyran, 3-methyl indolyl, 2-naphthyl, 3-pyridyl, 4-pyridyl, 3-thienyl; R3 is R2 or C3-8alkyl, R4 is C1-3alkyl; and R5 is NH2, OH, NHOH, NHOCH3, N(CH3)OH, N(CH3)OCH3, NHCH2CH3, NH(CH2CH3), NHCH2(2,4-(OCH3)2Ph, NHCH2(4-NO2)Ph, NHN(CH3)2, proline, or 2-hydroxymethyl pyrrolidine.
Another embodiment of the present invention provides a method for the treatment of a neoplastic disease comprising the step of administering to an individual in need of such treatment a pharmacologically effective dose of (S,S,R)-(xe2x88x92)-actinonin or other chemical compound disclosed herein or a pharmaceutically acceptable salt or hydrate thereof.
Yet another embodiment of the present invention provides a method of inhibiting the growth of a tumor cell comprising the step of contacting said cell with a pharmacologically effective dose of (S,S,R)-(xe2x88x92)-actinonin or other chemical compound disclosed herein or a pharmaceutically acceptable salt or hydrate thereof.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.